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protein metals links
Metal transport regulator PDB id
2fwu
Jmol
Contents
Protein chain
157 a.a. *
Metals
_CA ×2
* Residue conservation analysis
PDB id:
2fwu
Name: Metal transport regulator
Title: Second ca2+ binding domain of the na,ca-exchanger (ncx1)
Structure: Sodium/calcium exchanger 1. Chain: a. Fragment: cbd2, ca2+ binding domain 2. Synonym: na(+)/ca(2+)-exchange protein 1. Engineered: yes
Source: Canis lupus familiaris. Dog. Organism_taxid: 9615. Strain: familiaris. Gene: ncx1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
NMR struc: 20 models
Authors: M.Hilge,G.W.Vuister,J.Aelen
Key ref:
M.Hilge et al. (2006). Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors. Mol Cell, 22, 15-25. PubMed id: 16600866 DOI: 10.1016/j.molcel.2006.03.008
Date:
03-Feb-06     Release date:   18-Apr-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P23685  (NAC1_CANFA) -  Sodium/calcium exchanger 1
Seq:
Struc: 		 
Seq:
Struc: 		970 a.a.
157 a.a.
Key:    PfamA domain  Secondary structure

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     integral to membrane   1 term 
  Biological process     cell communication   1 term 

 

 
DOI no: 10.1016/j.molcel.2006.03.008 Mol Cell 22:15-25 (2006)
PubMed id: 16600866  
 
 
Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors.
M.Hilge, J.Aelen, G.W.Vuister.
 
  ABSTRACT  
 
The plasma membrane Na+/Ca2+ exchanger (NCX) is almost certainly the major Ca2+ extrusion mechanism in cardiac myocytes. Binding of Na+ and Ca2+ ions to its large cytosolic loop regulates ion transport of the exchanger. We determined the solution structures of two Ca2+ binding domains (CBD1 and CBD2) that, together with an alpha-catenin-like domain (CLD), form the regulatory exchanger loop. CBD1 and CBD2 are very similar in the Ca2+ bound state and describe the Calx-beta motif. Strikingly, in the absence of Ca2+, the upper half of CBD1 unfolds while CBD2 maintains its structural integrity. Together with a 7-fold higher affinity for Ca2+, this suggests that CBD1 is the primary Ca2+ sensor. Specific point mutations in either domain largely allow the interchange of their functionality and uncover the mechanism underlying Ca2+ sensing in NCX.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overall Architecture of NCX and Constructs Used in This Study 		Figure 4.
Figure 4. Biochemical Analyses of Ca^2+ Binding Sites
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 22, 15-25) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21209335 S.A.John, B.Ribalet, J.N.Weiss, K.D.Philipson, and M.Ottolia (2011).
Ca2+-dependent structural rearrangements within Na+-Ca2+ exchanger dimers.
  Proc Natl Acad Sci U S A, 108, 1699-1704.  
20298697 C.Zamparelli, N.Macquaide, G.Colotti, D.Verzili, T.Seidler, G.L.Smith, and E.Chiancone (2010).
Activation of the cardiac Na(+)-Ca(2+) exchanger by sorcin via the interaction of the respective Ca(2+)-binding domains.
  J Mol Cell Cardiol, 49, 132-141.  
19815561 M.Wu, H.D.Le, M.Wang, V.Yurkov, A.Omelchenko, M.Hnatowich, J.Nix, L.V.Hryshko, and L.Zheng (2010).
Crystal structures of progressive Ca2+ binding states of the Ca2+ sensor Ca2+ binding domain 1 (CBD1) from the CALX Na+/Ca2+ exchanger reveal incremental conformational transitions.
  J Biol Chem, 285, 2554-2561.  
  20624858 T.Yusifov, A.D.Javaherian, A.Pantazis, C.S.Gandhi, and R.Olcese (2010).
The RCK1 domain of the human BKCa channel transduces Ca2+ binding into structural rearrangements.
  J Gen Physiol, 136, 189-202.  
20187120 V.Breukels, and G.W.Vuister (2010).
Binding of calcium is sensed structurally and dynamically throughout the second calcium-binding domain of the sodium/calcium exchanger.
  Proteins, 78, 1813-1824.  
19395557 E.Janowski, R.Day, A.Kraev, J.C.Roder, L.Cleemann, and M.Morad (2009).
beta-adrenergic regulation of a novel isoform of NCX: sequence and expression of shark heart NCX in human kidney cells.
  Am J Physiol Heart Circ Physiol, 296, H1994-H2006.  
19141619 L.Boyman, H.Mikhasenko, R.Hiller, and D.Khananshvili (2009).
Kinetic and Equilibrium Properties of Regulatory Calcium Sensors of NCX1 Protein.
  J Biol Chem, 284, 6185-6193.  
19667209 M.Hilge, J.Aelen, A.Foarce, A.Perrakis, and G.W.Vuister (2009).
Ca2+ regulation in the Na+/Ca2+ exchanger features a dual electrostatic switch mechanism.
  Proc Natl Acad Sci U S A, 106, 14333-14338.
PDB codes: 2kls 2klt
19801651 M.Ottolia, D.A.Nicoll, and K.D.Philipson (2009).
Roles of two Ca2+-binding domains in regulation of the cardiac Na+-Ca2+ exchanger.
  J Biol Chem, 284, 32735-32741.  
19622870 N.Alonso-García, A.Inglés-Prieto, A.Sonnenberg, and J.M.de Pereda (2009).
Structure of the Calx-beta domain of the integrin beta4 subunit: insights into function and cation-independent stability.
  Acta Crystallogr D Biol Crystallogr, 65, 858-871.
PDB codes: 3fq4 3fso 3h6a
19332552 V.Chaptal, M.Ottolia, G.Mercado-Besserer, D.A.Nicoll, K.D.Philipson, and J.Abramson (2009).
Structure and functional analysis of a Ca2+ sensor mutant of the na+/ca2+ exchanger.
  J Biol Chem, 284, 14688-14692.
PDB code: 3gin
19158404 X.Q.Zhang, J.Wang, L.L.Carl, J.Song, B.A.Ahlers, and J.Y.Cheung (2009).
Phospholemman regulates cardiac Na+/Ca2+ exchanger by interacting with the exchanger's proximal linker domain.
  Am J Physiol Cell Physiol, 296, C911-C921.  
18280495 E.Johnson, L.Bruschweiler-Li, S.A.Showalter, G.W.Vuister, F.Zhang, and R.Brüschweiler (2008).
Structure and dynamics of Ca2+-binding domain 1 of the Na+/Ca2+ exchanger in the presence and in the absence of Ca2+.
  J Mol Biol, 377, 945-955.  
  19052365 M.Mima, C.Kawai, K.Paku, K.Tomoo, T.Ishida, S.Sugiyama, H.Matsumura, T.Kitatani, H.Y.Yoshikawa, S.Maki, H.Adachi, K.Takano, S.Murakami, T.Inoue, Y.Mori, S.Kita, and T.Iwamoto (2008).
Crystallization and preliminary X-ray crystallographic analysis of Ca2+-free primary Ca2+-sensor of Na+/Ca2+ exchanger.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 1125-1127.  
18550702 O.Chernysh, M.Condrescu, and J.P.Reeves (2008).
Sodium-dependent inactivation of sodium/calcium exchange in transfected Chinese hamster ovary cells.
  Am J Physiol Cell Physiol, 295, C872-C882.  
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 21, 1.  
17912755 P.M.Mohan, S.Mukherjee, and K.V.Chary (2008).
Differential native state ruggedness of the two Ca2+-binding domains in a Ca2+ sensor protein.
  Proteins, 70, 1147-1153.  
18172600 R.DiPolo, and L.Beaugé (2008).
In the squid axon Na+/Ca2+ exchanger the state of the Ca i-regulatory site influences the affinities of the intra- and extracellular transport sites for Na+ and Ca2+.
  Pflugers Arch, 456, 623-633.  
18550703 Y.Xie, M.Ottolia, S.A.John, J.N.Chen, and K.D.Philipson (2008).
Conformational changes of a Ca2+-binding domain of the Na+/Ca2+ exchanger monitored by FRET in transgenic zebrafish heart.
  Am J Physiol Cell Physiol, 295, C388-C393.  
17446448 A.M.Ruknudin, and E.G.Lakatta (2007).
The regulation of the Na/Ca exchanger and plasmalemmal Ca2+ ATPase by other proteins.
  Ann N Y Acad Sci, 1099, 86.  
17332076 C.Ryan, G.Shaw, and P.M.Hardwicke (2007).
Effect of Ca2+ on protein kinase A-mediated phosphorylation of a specific serine residue in an expressed peptide containing the Ca2+-regulatory domain of scallop muscle Na+/Ca2+ exchanger.
  Ann N Y Acad Sci, 1099, 43-52.  
17303833 D.A.Nicoll, X.Ren, M.Ottolia, M.Phillips, A.R.Paredes, J.Abramson, and K.D.Philipson (2007).
What we know about the structure of NCX1 and how it relates to its function.
  Ann N Y Acad Sci, 1099, 1-6.  
17290287 D.Noble, and A.Herchuelz (2007).
Role of Na/Ca exchange and the plasma membrane Ca2+-ATPase in cell function. Conference on Na/Ca exchange.
  EMBO Rep, 8, 228-232.  
17962412 G.M.Besserer, M.Ottolia, D.A.Nicoll, V.Chaptal, D.Cascio, K.D.Philipson, and J.Abramson (2007).
The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis.
  Proc Natl Acad Sci U S A, 104, 18467-18472.
PDB codes: 2qvk 2qvm
17347334 M.Hilge, J.Aelen, A.Perrakis, and G.W.Vuister (2007).
Structural basis for Ca2+ regulation in the Na+/Ca2+ exchanger.
  Ann N Y Acad Sci, 1099, 7.  
17158867 M.Ottolia, S.John, X.Ren, and K.D.Philipson (2007).
Fluorescent Na+-Ca+ exchangers: electrophysiological and optical characterization.
  J Biol Chem, 282, 3695-3701.  
18003903 M.P.Blaustein, T.H.Charpentier, and D.J.Weber (2007).
Getting a grip on calcium regulation.
  Proc Natl Acad Sci U S A, 104, 18349-18350.  
17917108 R.Gomez-Villafuertes, B.Mellström, and J.R.Naranjo (2007).
Searching for a role of NCX/NCKX exchangers in neurodegeneration.
  Mol Neurobiol, 35, 195-202.  
16774926 D.A.Nicoll, M.R.Sawaya, S.Kwon, D.Cascio, K.D.Philipson, and J.Abramson (2006).
The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif.
  J Biol Chem, 281, 21577-21581.
PDB code: 2dpk
17038313 J.Y.Lee, F.Visser, J.S.Lee, K.H.Lee, J.W.Soh, W.K.Ho, J.Lytton, and S.H.Lee (2006).
Protein kinase C-dependent enhancement of activity of rat brain NCKX2 heterologously expressed in HEK293 cells.
  J Biol Chem, 281, 39205-39216.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.